Iwata Keiko, Nakabayashi Kazuhiko, Ishiwata Keisuke, Nakamura Kazuhiko, Kameno Yosuke, Hata Kenichiro, Matsuzaki Hideo
Division of Development of Mental Functions, Research Center for Child Mental Development, University of Fukui, Fukui, Japan.
Department of Functional Brain Activities, United Graduate School of Child Development, Hamamatsu University School of Medicine, Osaka University, Kanazawa University, Chiba University, and University of Fukui, Osaka, Japan.
Psychiatry Clin Neurosci. 2025 Jul;79(7):415-424. doi: 10.1111/pcn.13830. Epub 2025 Apr 24.
Autism spectrum disorder (ASD) has a strong genetic basis, yet its genetic complexities remain elusive. Current research highlights environmental factors and epigenetic processes, such as DNA methylation, as crucial in ASD development. This exploratory study addresses a gap in understanding epigenetic regulation in the dorsal raphe (DR)-a region regulating multiple neurotransmitters and implicated in ASD-by examining DNA methylation profiles in postmortem ASD and control brains.
We comprehensively analyzed genome-wide DNA methylation profiles in the DR brain region (seven controls and five ASD) using the Infinium HumanMethylation450 BeadChip (Illumina). Additionally, quantitative polymerase chain reaction was used to measure messenger RNA levels of differentially methylated genes in ASD (11 controls and six ASD).
We identified differentially methylated regions (DMRs) between ASD and controls. These DMRs were located among various genomic regions, including promoters, gene bodies, and intergenic regions. Notably, we found hypermethylation in genes related to olfaction (e.g. OR2C3), which is regulated by serotonin. Additionally, we observed that the hypomethylation of promoter-associated CpG islands in RABGGTB, a gene related to autophagy and synaptic function, corresponded with its increased expression.
Our findings reveal extensive DNA methylation changes in critical genomic regions, shedding light on potential mechanisms underlying ASD. The identification of RABGGTB as a novel candidate gene, not listed in the SFARI database, underscores its significance and warrants further research to explore its role in ASD diagnosis. This study enhances our understanding of the epigenetic landscape in ASD, emphasizing the interplay between genetic and environmental factors in its pathophysiology.
自闭症谱系障碍（ASD）具有强大的遗传基础，但其遗传复杂性仍难以捉摸。当前研究强调环境因素和表观遗传过程，如DNA甲基化，在ASD发展中至关重要。这项探索性研究通过检查死后ASD和对照大脑中的DNA甲基化谱，解决了在理解中缝背核（DR）（一个调节多种神经递质并与ASD有关的区域）表观遗传调控方面的空白。
我们使用Infinium HumanMethylation450 BeadChip（Illumina）全面分析了DR脑区（七个对照和五个ASD）的全基因组DNA甲基化谱。此外，使用定量聚合酶链反应来测量ASD中差异甲基化基因的信使RNA水平（11个对照和六个ASD）。
我们确定了ASD和对照之间的差异甲基化区域（DMR）。这些DMR位于各种基因组区域，包括启动子、基因体和基因间区域。值得注意的是，我们发现与嗅觉相关的基因（如OR2C3）存在高甲基化，该基因受血清素调节。此外，我们观察到与自噬和突触功能相关的基因RABGGTB中启动子相关CpG岛的低甲基化与其表达增加相对应。
我们的研究结果揭示了关键基因组区域广泛的DNA甲基化变化，揭示了ASD潜在的机制。RABGGTB作为一个未在SFARI数据库中列出的新候选基因的鉴定，强调了其重要性，并值得进一步研究以探索其在ASD诊断中的作用。这项研究增强了我们对ASD表观遗传格局的理解，强调了遗传和环境因素在其病理生理学中的相互作用。
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